RT Journal Article
SR Electronic
T1 PGM3 inhibition Shows cooperative Effects With Erastin inducing Pancreatic cancer cell death via activation of the Unfolded Protein Response
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.03.19.533311
DO 10.1101/2023.03.19.533311
A1 Zerbato, Barbara
A1 Gobbi, Maximilian
A1 Ludwig, Tobias
A1 Brancato, Virginia
A1 Pessina, Alex
A1 Brambilla, Luca
A1 Wegner, Andre
A1 Chiaradonna, Ferdinando
YR 2023
UL http://biorxiv.org/content/early/2023/03/23/2023.03.19.533311.abstract
AB Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor patient prognosis. Remarkably, PDAC is one of the most aggressive and deadly tumor types and is notorious for its resistance to all types of treatment. PDAC resistance is frequently associated with a wide metabolic rewiring and in particular of the glycolytic branch named Hexosamine Biosynthetic Pathway (HBP). Here we show the effect of the combined treatment between an HBP’s Phosphoglucomutase 3 (PGM3) enzyme inhibitor, named FR054, and erastin (ERA), a recognized ferroptosis inducer, on PDAC cell growth and survival. Noteworthy, the combined treatment applied to PDAC cell lines induces a significant decrease in cell proliferation and a concurrent enhancement of cell death. Furthermore, we show that this combined treatment induces Unfolded Protein Response (UPR), NFE2 Like BZIP Transcription Factor 2 (NRF2) activation, a change in cellular redox state, a greater sensitivity to oxidative stress, a major dependence on glutamine metabolism, and finally ferroptosis cell death. Our study discloses that HBP inhibition enhances, through UPR activation, the ERA effect and therefore might be a novel anticancer mechanism to be exploited as PDAC therapy.Competing Interest StatementThe authors have declared no competing interest.